One of Waller’s intended recruits is Flag’s girlfriend Dr. June Moone, an archaeologist possessed by a witch-goddess known as the “Enchantress”. Enchantress quickly turns on Waller, deciding to eradicate humankind with a mystical weapon for imprisoning her. She besieges Midway City by transforming its populace into a horde of monsters, and summons her brother Incubus to assist her. Waller then deploys the squad to extract a high-profile mark from Midway, which is reported to be under a terrorist attack.

Harley’s homicidal lover, the Joker, finds out about her predicament and tortures Belle Reve Security Officer Griggs into leading him to the facility where the nano bombs are made. There, he blackmails Dr. Van Criss into disabling Harley’s bomb. On approach, the squad’s helicopter is shot down, forcing them to proceed on foot to their target. Boomerang inaccurately convinces Slipknot that the bombs are a ruse to keep them in check; Slipknot attempts to escape and Flag kills him via his nano bomb, while the squad is attacked by Enchantress’ minions. They eventually manage to fight their way through to a safe room, where they learn that their mark is Waller herself, who is attempting to cover up her involvement in Enchantress’ siege.

The squad escorts Waller to a rooftop for extraction, but the arriving helicopter has been hijacked by the Joker and his men, who open fire on the squad while Harley climbs aboard upon Dr. Van Criss disarming the bomb. However, Waller’s men shoot down the helicopter, and Harley falls out while the Joker is presumed dead, after which Harley rejoins the squad. Alerted to Waller’s whereabouts, Enchantress’ minions arrive and kidnap her. Deadshot finds Waller’s confidential files and learns the truth about Enchantress. Flag is then forced to confess the truth, causing the squad members to abandon him. With Waller compromised, Flag relieves the squad of the mission, but chooses to continue. Realizing they have an opportunity to prove themselves, they soon rejoin him and locate Enchantress at a partially-flooded subway station. Killer Croc and a group of Navy SEALs, led by Lieutenant GQ Edwards, go underwater to plant a bomb underneath Incubus. El Diablo embraces his abilities and manages to distract Incubus long enough for the bomb to detonate underneath, killing them both as well as Edwards.

The remaining squad members battle Enchantress together, but are ultimately defeated. Enchantress offers to fulfill their deepest desires in exchange for their allegiance, and Harley feigns interest in order to get close enough to cut out Enchantress’ heart. Killer Croc then throws explosives into Enchantress’ weapon and Deadshot shoots them, destroying the device. Flag takes Enchantress’ heart and crushes it, finally freeing June from the curse. Waller, still alive, emerges, and the squad members are returned to Belle Reve with ten years off their sentences. All but Captain Boomerang are allowed special privileges. The Joker, alive and unscathed, breaks into the penitentiary and rescues Harley. In a mid-credits scene, Waller meets with Bruce Wayne, who agrees to protect her from the backlash against her role in Enchantress’ rampage in exchange for access to the government’s files on the expanding metahuman community.